1. Field of the Invention
The present invention provides phosphorous containing derivatives of epipodophyllotoxin glucoside aldehyde or ketone condensation products which have the ability to inhibit transplanted tumors in experimental animals and to the therapeutic anti-tumor use and pharmaceutical dosage forms of these new agents.
2. Description of the Prior Art
Etoposide (VP-16, Ia) and teniposide (VM-26, II) are clinically useful anticancer agents derived from the naturally occurring lignan, podophyllotoxin (III). The numbering system used for nomenclature purposes is shown in Formula III. Note that podophyllotoxin and etoposide, an epipodophyllotoxin derivative, are epimeric at the 4-position. Etoposide and teniposide are active in the treatment of a variety of cancers including small cell lung cancer, non-lymphocytic leukemia, and nonseminomatous testicular cancer (AMA Drug Evaluations, 5th Edition, American Medical Association, 1983, Chicago, Ill. p. 1554-1555). ##STR1##
Etoposide and teniposide, and methods for producing them, are disclosed in U.S. Pat. No. 3,524,844 to Keller-Juslen et al. which similarly discloses a series of compounds having Formula I wherein R.sup.4 has the broader definition given below with respect to Formula V. Etoposide-3', 4'-quinone Formula IV, is derived from etoposide by oxidation as described by Josef Nemec in U.S. Pat. No. 4,609,644, patented Sept. 2, 1986. The quinone IVa has been implicated as a reactive intermediate in the metabolic activation of etoposide by rat liver and hela microsomal fractions (Van Maanen, J. M.; Holthuis, J. J.; Gobas, F. et al. Proc. Am Assoc. Cancer Res. 1983, 24, 319), and also has been suggested as a bioalkylating agent in a report describing the metabolism of etoposide by mouse liver microsomes (see Haim, N.; Nemec, J.; Roman, J.; Sinha, B. K. presented at the American Society for Pharmacology and Experimental Therapeutics meetings at Boston, Mass., Aug. 18-22, 1985). Etoposide-3', 4'-quinone has been generated from electrochemical oxidation of etoposide (see Holthuis, J. J.; Van Oort, W. J.; Romkens, F.M.G.M.; Renema, J. J. J. Electroanal. Chem. 1985, 1984, 317). Etoposide-3', 4'-quinone IVa serves as the starting material for our preparation of the etoposide phosphorous derivatives of the present invention. ##STR2##
.alpha.-Diketones such as butane-2,3-dione, benzil, and ortho-quinones such as 9,10-phenanthraquinone are known to react with trialkyl-and triarylphosphites of the formula (RO).sub.3 P to yield cyclic oxyphosphoranes (F. Ramirez and N. B. Desai, J. Amer. Chem. Soc. 82, 2652 (1960)). More recently the reaction has been applied to a more complex ortho-quinone derived from pyrrolo(3,2-e)indole (Magnus et al., J. Chem. Soc., Chem. Commun. 1162-1164 (1986)).
Phosphines in which the phosphorous atom is part of a strained cyclic structure such as 1-phenyl-2,2,4,4-tetramethylphosphetidine react with highly reactive ketones such as hexafluoroacetone to yield bicyclic oxyphosphoranes (L. D. Quin, "The Heterocyclic Chemistry of Phosphorous" John Wiley and Sons, New York 1981 pp. 168-170).